Since the discovery of anti-tumor activity of cisdiamminedichloroplatinum(II) known generically as cisplatin by B. Rosenberg (nature 205, 698(1965)), comprehensive studies including its clinical tests have been performed leading to FDA approval of cisplatin as a chemotherapeutic anti-tumor agent. Currently cisplatin is one of the most widely used anti-tumor agents and in particular, is effective for testicular, ovarian, bladder, head and neck, and lung cancers, but because of its high toxicity (LD.sub.50 =13 mg/Kg), its use is limited. On the other hand, carboplatin, cis-(NH.sub.3).sub.2 Pt(CBDCA)(CBDCA=1,1-dicyclobutanedicarboxylate) which was approved by FDA in 1989, has much lower toxicity (LD.sub.50 =180 mg/Kg) compared with cisplatin, but its anti-tumor activity is lower and more expensive than cisplatin. Therefore, a great deal of researches for searching new anti-tumor agents with higher activity and lower toxicity than cisplatin or carboplatin is actively underway.
The exact mechanisms of anti-tumor activity and toxicity of cisplatin are yet to be known, but the recent reviews (Pharmac. Ther. 25, 297-326(1984); Chem. Rev. 87, 1153-1181 (1987)) show that when cisplatin is injected into the blood plasma, it is only partly hydrolyzed and due to the high concentration of chloride ion (.about.100 mM) in the plasma, its major portion penetrates into the cell as neutral molecule. However, since the chloride concentration in the cell is very low (.about.4 mM), the majority of the penetrated cisplatin molecules are subjected to hydrolysis with the chloride ligand dissociated, and consequently aquated platinum cations are presumed to combine with DNA in the cell, which prevents replication of DNA leading to killing cells. The platinum complex ions do not distinguish normal cells from tumor cells yielding cytotoxicity, and furthermore, the dimeric and other oligomeric platinum species resultant from the hydrolysis of cisplatin are known to cause severe side effects such as nephrotoxicity.
In spite of a great deal of researches in this field to develop new compounds with higher anti-tumor activity and significantly lower toxicity, no one has been yet successful. The present inventors have now found that some novel platinum complexes chelated by dicarboxylic acid derived from malonic acid as shown in the above formula I are appropriate candidates meeting such criteria.